Although up to 90% of cocaine-dependent individuals also may be addicted to alcohol, few pharmacotherapy studies have been undertaken to identify efficacious agents for the combined treatment of these commonly occurring comorbid disorders. Advances in the neurosciences show that substance-induced brain reward is mediated through mesolimbic dopamine (DA) pathways and expressed via gamma-aminobutyric acid (GABA) efferents that project from the nucleus accumbens to the cortex. These GABA efferents are themselves under the tonic inhibition of glutaminergic excitatory amino acid (EAA) pathways. Recently, we hypothesized that topiramate, a sulfamate substituted fructo-pyranose derivative, through facilitation of mesocortical GABAergic function and inhibition of EAAs, should more reliably diminish substance-induced brain reward because both DA release and its midbrain expression will be diminished. As evidence in support of this hypothesis, we have demonstrated in a randomized, controlled clinical trial that topiramate is an effective treatment for alcohol dependence. Extending this concept to other substance-abuse disorders, we predict that, like in alcohol dependence, and as suggested by preclinical studies, topiramate also will be effective as a treatment for cocaine dependence, as well as for comorbid disorder. We, therefore, propose to conduct a randomized, double-blind, controlled clinical trial to determine the safety and efficacy of topiramate in the treatment of comorbid cocaine and alcohol dependence. A multi-ethnic, multi-gender study group consisting of 180 cocaine and alcohol dependent individuals will receive combined Cognitive Behavioral Therapy (CBT) for cocaine and alcohol use cessation. Subjects will be randomized to receive either adjuvant treatment with the anti-craving medication topiramate (300 mg/day) or placebo. The treatment period will be 12 weeks, and follow-up will occur at 2 weeks and 1, 2, and 3 months post-trial cessation. The primary specific aims of this study are to test two predictions of our hypothesis: 1) The Topiramate group will be superior to the Placebo group on the following outcome measures: a) increasing the weekly mean proportion of cocaine-free days (assessed by self-report of use and urine assays for benzoylecgonine, the major metabolite of cocaine), and b) decreasing self-reported drinking (measured by Drinks/Day, Drinks/Drinking Day, and Percent Days Abstinent) and biochemical markers of alcohol consumption, plasma carbohydrate-deficient transferrin and gamma-glutamyl transferase. 2) The Topiramate group will be superior to the Placebo group at decreasing craving for cocaine and alcohol (measured using the Cocaine Craving Questionnaire-Now-CCQ, and the Obsessive Compulsive Drinking Scale - OCDS), and the amount of craving reduction will be associated with reduced intake of each and both abused substances. We also will test the additional secondary predictions that: 3) Topiramate, compared with placebo, will be associated with an improvement in psychosocial functioning as exemplified by improved: a) general well-being; b) social functioning, and c) enhanced quality of life. Our objectives support NIH's mission to understand the basic mechanisms that underpin substance dependence, and to develop efficacious treatments for individuals with comorbid cocaine and alcohol dependence.